Long-term ethanol self-administration by the nonhuman primate, Macaca fascicularis, decreases the benzodiazepine sensitivity of amygdala GABA A receptors

Nancy J. Anderson, James B. Daunais, David P. Friedman, Kathleen (Kathy) Grant, Brian A. McCool

    Research output: Contribution to journalArticle

    22 Citations (Scopus)

    Abstract

    Background: Rodent models of chronic alcohol exposure are typically constrained to relatively short periods of forced ethanol due to the lifespan of these animals. Nonhuman primate models, particularly those employing long-term self-administration, are conceptually more similar to human alcoholic individuals. Methods: We performed whole-cell patch clamp recordings on acutely dissociated amygdala neurons isolated from cynomolgus macaque coronal temporal lobe slices. Slices were prepared from control monkeys or monkeys allowed to self-administer oral ethanol for 18 months. Flunitrazepam and acute ethanol modulation of currents gated by exogenous γ-aminobutyric acid (GABA) application was assessed in these isolated neurons. Complementary experiments were performed on amygdala total RNA using quantitative real-time reverse transcription/polymerase chain reaction to understand potential ethanol-dependent adaptations to subunit composition. Results: γ-Aminobutyric acid-gated currents from ethanol-exposed macaque amygdala neurons exhibited reduced modulation by flunitrazepam compared with control neurons. However, this was specific for benzodiazepines as the modest inhibition of GABA-gated currents by acute ethanol was not affected by the chronic ethanol consumption. We also measured mRNA expression levels for the β, γ, and δ subunits in total amygdala RNA isolated from control and ethanol-drinking animals. β1 and γ2 expression was significantly reduced in samples from ethanol-exposed amygdala. Conclusions: Our findings demonstrate that chronic ethanol self-administration reduces the benzodiazepine sensitivity of amygdala GABAA receptors. This reduced sensitivity may be the result of decreased expression of an amygdala γ subunit. These findings suggest that, while rodent and nonhuman primate models of chronic ethanol exposure share many characteristics, the specific molecular adaptations associated with the amygdala GABAergic system may not be identical.

    Original languageEnglish (US)
    Pages (from-to)1061-1070
    Number of pages10
    JournalAlcoholism: Clinical and Experimental Research
    Volume31
    Issue number6
    DOIs
    StatePublished - Jun 2007

    Fingerprint

    Aminobutyrates
    Self Administration
    Macaca fascicularis
    Amygdala
    Benzodiazepines
    Primates
    Ethanol
    Neurons
    Flunitrazepam
    Macaca
    Haplorhini
    Rodentia
    Animals
    Modulation
    RNA
    Polymerase chain reaction
    Clamping devices
    GABA-A Receptors
    Temporal Lobe
    Transcription

    Keywords

    • Flunitrazepam
    • Isolated Neurons
    • Real-Time RT-PCR
    • Whole-Cell Patch-Clamp Electrophysiology

    ASJC Scopus subject areas

    • Medicine (miscellaneous)
    • Toxicology

    Cite this

    Long-term ethanol self-administration by the nonhuman primate, Macaca fascicularis, decreases the benzodiazepine sensitivity of amygdala GABA A receptors. / Anderson, Nancy J.; Daunais, James B.; Friedman, David P.; Grant, Kathleen (Kathy); McCool, Brian A.

    In: Alcoholism: Clinical and Experimental Research, Vol. 31, No. 6, 06.2007, p. 1061-1070.

    Research output: Contribution to journalArticle

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    abstract = "Background: Rodent models of chronic alcohol exposure are typically constrained to relatively short periods of forced ethanol due to the lifespan of these animals. Nonhuman primate models, particularly those employing long-term self-administration, are conceptually more similar to human alcoholic individuals. Methods: We performed whole-cell patch clamp recordings on acutely dissociated amygdala neurons isolated from cynomolgus macaque coronal temporal lobe slices. Slices were prepared from control monkeys or monkeys allowed to self-administer oral ethanol for 18 months. Flunitrazepam and acute ethanol modulation of currents gated by exogenous γ-aminobutyric acid (GABA) application was assessed in these isolated neurons. Complementary experiments were performed on amygdala total RNA using quantitative real-time reverse transcription/polymerase chain reaction to understand potential ethanol-dependent adaptations to subunit composition. Results: γ-Aminobutyric acid-gated currents from ethanol-exposed macaque amygdala neurons exhibited reduced modulation by flunitrazepam compared with control neurons. However, this was specific for benzodiazepines as the modest inhibition of GABA-gated currents by acute ethanol was not affected by the chronic ethanol consumption. We also measured mRNA expression levels for the β, γ, and δ subunits in total amygdala RNA isolated from control and ethanol-drinking animals. β1 and γ2 expression was significantly reduced in samples from ethanol-exposed amygdala. Conclusions: Our findings demonstrate that chronic ethanol self-administration reduces the benzodiazepine sensitivity of amygdala GABAA receptors. This reduced sensitivity may be the result of decreased expression of an amygdala γ subunit. These findings suggest that, while rodent and nonhuman primate models of chronic ethanol exposure share many characteristics, the specific molecular adaptations associated with the amygdala GABAergic system may not be identical.",
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    AU - Grant, Kathleen (Kathy)

    AU - McCool, Brian A.

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